Abstract Presently an estimated 25.9 million Americans suffer from asthma and over half have at least one asthma attack per year. Few novel therapeutics have been approved for targeting airway smooth muscle relaxation or lung inflammation in the last 40 years. Recent studies found that 60% of moderate asthmatics and 70% of severe asthmatics report using complementary and alternative medicine (CAM) to self-treat their asthma symptoms. The exact mechanism of action of these agents is unclear but may involve attenuation of allergic response (IgE levels), anti-inflammatory and antioxidant effects, and/or direct effects on airway smooth muscle. Clinical trials with chronic oral ginger therapy have demonstrated safe consumption of 2g per day for 28 days which resulted in the successful detection of the active components of ginger in human plasma and demonstrated an anti-proliferative and anti-inflammatory effect in human colon cancer and other inflammatory diseases in vivo and in airway cells in vitro. Thus, our central hypothesis is that ginger will prove efficacious in improving clinical symptoms of asthma and improve the tolerance to an inhaled methacholine bronchoconstrictive challenge due chronic reduction of lung inflammation. We will address two primary biological signatures that reflect the hypothesized mechanism of action of ginger components (i.e. inhibition of phospholipase C); (1) an increased tolerance to inhaled methacholine; and (2) a reduction in exhaled nitric oxide, a measure of lung inflammation. The specific aims are (1) to demonstrate the beneficial effects of oral ginger by an improved tolerance to inhaled methacholine over a 56 day study period; (2) demonstrate an improvement in lung inflammation reflected in reduced exhaled nitric oxide, eosinophilia and serum cytokine levels; (3) demonstrate the bioavailability of metabolites of the active components of ginger shown to have the largest inhibitory effect on phospholipase C; and (4) demonstrate the absence of adverse events and optimal dosing and dosing frequency. This proposal (a) is a pilot study to test a natural botanical substance widely used as a dietary supplement for which sufficient early stage data justifies further clinical testing, (b) measures the bioavailability and the natural product?s mechanism of proposed action will be assessed, (c) stems from compelling preclinical evidence for a potential health benefit, (d) investigates a natural substance widely used by the American public as a dietary supplement, and (e) is performed in a human clinical population with objective outcome measures of a biological signature. This translational study will define the parameters for a large scale clinical trial.